Date: 2016-05-18
Type of information: Treatment of the first patient
phase: 1
Announcement: treatment of the first patient
Company: Synthon (The Netherlands)
Product: SYD985 (HER2-targeting antibody-drug conjugate based on trastuzumab and Synthon’s proprietary cleavable linker-duocarmycin (vc-seco-DUBA) payload)
Action
mechanism: antibody drug conjugate. SYD985 is a HER2-targeting antibody drug conjugate (ADC) based on trastuzumab and Synthon’s proprietary cleavable linker-duocarmycin (vc-seco-DUBA) payload. SYD985 is the most advanced candidate in Synthon’s ADC portfolio, and has demonstrated unprecedented anti-tumor activity in preclinical breast and gastric cancer models with low expression of HER2 (HER2 2+ and HER2 1+). In vitro, SYD985 and T-DM1 (Kadcyla®) were studied in a panel of eight cell lines expressing different levels of HER2. In cell lines with high HER2 expression (characterized as HER2 3+) SYD985 and T-DM1 showed similar potencies. However, in cell lines with low or moderate HER2 expression (characterized as HER2 1+ and HER2 2+), SYD985 was substantially more potent than T-DM1. In vivo anti-tumor activity was assessed in a series of xenograft models using tumor cell lines and patient-derived breast-cancer tissues with varying HER2 expression levels (HER2 3+, HER2 2+ and HER2 1+). Both SYD985 and T-DM1 showed anti-tumor activity in the HER2 3+ models. SYD985 demonstrated very potent anti-tumor activity in the FISH-negative models that were either HER2 2+ or HER2 1+, contrary to T-DM1 which was completely inactive. In these moderate- or low-expressing HER2 tumor models, SYD985 was even able to induce complete tumor remission after a single dose of 3 mg/kg.
Disease: locally advanced or metastatic solid tumors including breast cancer, gastric cancer
Therapeutic area: Cancer - Oncology
Country: The Netherlands, Belgium, UK
Trial
details: This trial SYD985.001 is a two part first-in-human Phase I study. In the dose escalation part of the trial, safety and efficacy of SYD985 will be evaluated in patients with locally advanced or metastatic solid tumors of any origin. These are patients who have progressed on standard therapy or for whom no standard therapy exists. During part I (dose escalation) patients with solid tumors of any origin will be enrolled. For part II (expanded cohorts) enrollment is limited to patients with breast or gastric tumors with demonstrated HER2 expression and measurable disease lesions as per protocol defined criteria. (NCT02277717)
Latest
news: * On May 18, 2016, Synthon Biopharmaceuticals announced the initiation of the second part of its ongoing Phase I clinical trial with the investigational anti-HER2 antibody-drug conjugate (ADC) SYD985. The second part will see 48 additional heavily pre-treated patients with HER2-positive breast cancer enrolled into the SYD985.001 trial. Promising results were obtained in the dose-finding part of the Phase I trial in 33 cancer patients who were dosed with between 0.3 and 2.4 mg/kg of SYD985 every three weeks. Most noticeably, very high response rates and durable responses were observed in patients whose cancers were refractory to HER2-targeted agents, including trastuzumab (Herceptin®*) and trastuzumab emtansine (Kadcyla®*), following treatment with SYD985 at doses from 1.2 mg/kg onwards. Although data from the dose-finding part - which includes patients with solid tumors of any origin - will continue to be collected, evaluation of the larger cohort of 48 heavily pre-treated breast cancer patients with HER2-positive tumors (i.e. HER2 3+ or FISH-positive) has been initiated. Clinical evaluation in this heavily pre-treated patient population, whose cancers are refractory to multiple lines of registered HER2-targeting treatments including Herceptin® and Kadcyla®, will continue to collect data on efficacy, safety and tolerability of SYD985 treatment at a starting dose of 1.2 mg/kg. Data from this cohort will enable Synthon to design the first pivotal trial with SYD985 as suggested by several national regulatory authorities and subject to an ongoing EMA scientific advice request regarding the most optimal development pathway. Synthon will shortly submit a pre-IND (Investigational New Drug Application) meeting request to the FDA addressing the same topic, with the aim of extending this clinical development program to include U.S. clinical sites under an IND. * On September 28, 2015, Synthon Biopharmaceuticals reported positive initial results from the dose-escalation part of its ongoing first-in-human trial with SYD985. Partial responses were observed in breast cancer patients who are refractory to previous HER2-targeted treatments. The data were presented on 27 September 2015 during the European Cancer Congress in Vienna, Austria. In the ongoing dose-escalation part of the trial, safety and efficacy of SYD985 have been evaluated in patients with locally advanced or metastatic solid tumors of any origin. The patients were enrolled in Radboud University Medical Center (Nijmegen, the Netherlands), the Jules Bordet Institute (Brussels, Belgium) and the Institute of Cancer Research at The Royal Marsden Hospital (London, United Kingdom). Partial responses are observed in breast cancer patients who are refractory to previous HER2-targeted treatments, including trastuzumab emtansine (T-DM1). In addition, efficacy was reported in a HER2 2+ / FISH-negative breast cancer patient. Although the maximum tolerated dose has not yet been reached and the dose escalation part is ongoing, initial results, including safety, tolerability and pharmacokinetics, were reported on investigated dose cohorts up to 2.4 mg/kg. Continuation of the dose-escalation part of the trial will further define the safety and efficacy profile of SYD985 before selection of the recommended Phase II dose and initiation of the expanded patient cohort part. These expanded cohorts will include breast cancer and gastric cancer patients with at least HER2 1+ expression. Apart from that, patients will be recruited in indications where presently no effective anti-HER2 therapy is available, including lung cancer, endometrial cancer and bladder cancer. * On November 25, 2014, Synthon Biopharmaceuticals announced that the first patients with metastatic solid tumors have commenced treatment with its investigational anti-HER2 antibody-drug conjugate (ADC), SYD985. First patients for this trial are being enrolled in leading European oncology centers Radboud University Medical Center (Nijmegen, the Netherlands), the Jules Bordet Institute (Brussels, Belgium) and the Institute of Cancer Research at The Royal Marsden Hospital (London, United Kingdom). The trial will recruit at least 76 patients and more centers are expected to join the trial in 2015.
